Abstract

Lysine acetyltransferases (KATs) and lysine deacetylases (KDACs) are known to cooperate with the glucocorticoid receptor (GR) to regulate transcription. The current model of GR-mediated transcription classifies KATs as coactivators as they acetylate histones to form an open chromatin conformation and casts KDACs as corepressors that deacetylate histones and condense chromatin. Our recent studies have challenged this long-standing model. In the current study, we show that KDACs act as versatile coregulators, facilitating both the onset and maintenance of GC-induced transcriptional activation and repression. Through siRNA depletion studies, we define KDAC1 as the predominant Class I KDAC for efficient transactivation of a majority of the GR-target genes tested. KDACs 1 and 2 co-operate with each other to activate and repress a few target genes, however KDAC2 alone is not sufficient for activation or repression of the genes, thus questioning the functional redundancy of KDACs 1 and 2. Additionally, we found that there is a unique population of KDAC2 that does not associate with KDAC1 in our cell line. Through a series of siRNA depletion studies, steroid receptor coactivator proteins (SRCs) were shown to be dispensable for GC-induced gene activation and SRC2 was not required for Dex-induced transcriptional repression. We performed ChIP assays to address the mechanism by which Class I KDACs facilitate transactivation and transrepression. At GC-activated genes we found that KDACs are constitutively present at the gene enhancers and that KDAC inhibition does not affect the binding of GR or SRC proteins to chromatin. However, KDACs do influence the histone methylation status of H3K4 at GREs of activated genes and TSSs of repressed genes. To explain the change in the methylation status of this marker, we depleted LSD1, the specific demethylase for mono- and demethylation of H3K4, and found that LSD1 action is required for GC-mediated transrepression. However it is unlikely that KDAC inhibition impairs GR transactivation through effects on LSD1. Glucocorticoid signaling regulates multiple vital biological processes. Glucocorticoids play a major role in regulating carbohydrate, protein and lipid metabolism. They increase hepatic gluconeogenesis to maintain blood glucose concentration in the fasting state. GCs also act as potent anti-inflammatory molecules, stimulate lung maturation in the developing fetus, and affect bone metabolism. Additionally, excess or deficiency of GCs can lead to a variety of psychological abnormalities, indicating their role in CNS functions. Our results indicate that pharmaceutical modulation of KDACs may impair proper glucocorticoid signaling and disrupt vital biological processes. Other steroid hormone receptors function similarly to GR in regulating gene expression and could also be impacted by KDAC inhibition, thus suggesting serious physiological implications in patients. Therefore, the possibility of endocrine modulation should be taken into account when using KDAC inhibitors in the clinic.

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